On July 31, 2009, Reddick was called up to the major leagues to replace Adam LaRoche, who had been traded. He made his major league debut that night, pinch-hitting for Rocco Baldelli in the ninth inning and grounding out against Cla Meredith of the Baltimore Orioles in his only at-bat. He recorded his first MLB hit in the next game, a double in the second inning off of David Hernandez. He doubled again later in the game against Chris Ray for his first multi-hit major league game. On August 2, 2009, he hit his first major league home run against Brian Bass. He was the first Red Sox outfielder to hit a home run within his first three games since Billy Conigliaro in 1969.

Reddick was optioned back to the Triple A-Pawtucket Red Sox on August 5. The move allowed a depleted Red Sox bullpen to use Billy Traber's services.[3] Reddick was recalled the very next day when Rocco Baldelli was placed on the disabled list with a left ankle contusion.

Reddick again started 2011 in Pawtucket but was recalled on May 26, 2011, after Darnell McDonald was placed on the 15-day disabled list with a strained left quad.[4] He was able to stay in the majors after the Red Sox designated Cameron for assignment on June 29, 2011, effectively removing Cameron from the active and 40-man rosters, leaving room for Reddick. On August 7, 2011, he hit his first MLB walk-off hit against the New York Yankees, driving in McDonald in the bottom of the 10th inning.

Reddick began the year as the starting right fielder. On May 7, he was placed on the disabled list with a sprained right wrist, and was activated on May 31. Through most of the 2013 season, Reddick failed to retain the power he had from the previous season. Through August 8, he had hit .203 with only five home runs on the season. But on August 9, 2013, Reddick hit 3 home runs in a single game for the first time in his career in a 14-6 rout against the Toronto Blue Jays. On the next day, he homered twice more against Toronto. The total of five home runs in two games tied the Major League record for most home runs in consecutive games.[7] On August 26 Reddick was placed on the 15-day disabled list with an injured right wrist.[8] He returned on September 11. From August 9 to the end of the season, Reddick hit .284/.357/.514 with 7 HR and 19 RBI. In 114 total games, he hit .226/.307/.379 with 12 HR and 56 RBI.

After the season, Reddick underwent arthroscopic surgery on his wrist, which caused him to miss 37 games on the disabled list. Reddick arrived at spring training fully healthy in 2014.[9] On February 15, 2014, Reddick and the Athletics agreed upon a one-year $2.7 million deal, avoiding arbitration. Reddick announced that he would wear number 22 for the 2015 season so that Billy Butler could wear number 16.[10] Reddick signed with the Athletics for $4.1 million in 2015, and $6.575 million in 2016, his last year before qualifying for free agency.[11]

The Houston Astros signed Reddick to a four-year deal worth $52 million on November 23, 2016.[14] During the 2017 regular season, he appeared in 134 games for Houston, batting .314 with 13 home runs and 82 RBIs. The Astros clinched the AL West pennant with a 101-61 record, and eventually won the 2017 World Series.[15]